Principal Investigator: De-Maw Chuang
Section on Molecular Neurobiology
Dr. Chuang is the Chief of the Molecular Neurobiology Section of the Intramural Research Program, National Institute of Mental Health, National Institutes of Health in Bethesda, Maryland. He received his Ph.D. degree from the Molecular and Cellular Biology Program, State University of New York at Stony Brook. He did his postdoctoral training at the Roche Institute of Molecular Biology in Nutley, New Jersey.
Dr. Chuang’s current research centers on the neurobiology of mood stabilizing drugs, notably lithium, valproic acid and lamotrigine, which are used to treat bipolar mood disorder. His pioneering work demonstrated that treatment with lithium robustly protects cultured CNS neurons from glutamate-induced NMDA-receptor-mediated excitotoxicity, which has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. His recent research provided evidence that lithium and valproic acid, by inhibiting glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs), respectively, elicited neuroprotective, neurotrophic, anti-inflammatory and mood stabilizing effects, among others. His laboratory also reported the downstream mechanisms mediating these actions. His past and current work shows that lithium and valproic acid have beneficial effects in multiple animal models of neurodegenerative and neuropsychiatric disorders. His research goal is to explore the possibility that mood stabilizers have utility in treating neurodegenerative diseases in addition to bipolar disorder.
Dr. Chuang has received many honors and awards, including the NIH Director’s Award in 1997 in recognition of "his superb leadership and innovative research which advances the understanding of basic mechanisms involved in neurodegenerative and neuropsychiatric disorders". He is the recipient of the 2002 NARSAD Distinguished Investigator Award. He was also inducted into the Academia Sinica in Taiwan in 2006. Dr. Chuang is an Adjunct Professor of Psychiatry and Neuroscience at the Uniformed Services University of the Health Sciences in Bethesda, and a member of many scientific societies including the ACNP, FASEB and the Society for Neuroscience. He has published over 250 scientific articles in peer-reviewed journals including Proceedings of the National Academy of Sciences, Science, Nature Medicine, Journal of Neuroscience, Molecular Psychiatry, Journal of Biological Chemistry, Trends in Neurosciences, Annual Review of Pharmacology and Toxicology, and Pharmacological Reviews. Dr. Chuang was selected as the NIMH Outstanding Mentor in 2010 and 2011, and a Distinguished Alumnus of National Taiwan University in 2012.
The Molecular Neurobiology Section seeks to delineate novel neurobiological effects of mood stabilizing drugs notably lithium and valproic acid (VPA), and explore their therapeutic potential for serious CNS pathological conditions. Our central hypothesis is that lithium and VPA, by inhibiting glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs), respectively, trigger a spectrum of neurobiological changes. These include: the induction of neurotrophic and neuroprotective molecules; anti-inflammation; the generation of antidepressant, antimanic, and antianxiety effects; angiogenesis; neurogenesis; the promotion of stem cell migration; the regulation of microRNA (miRNA) expression; and the improvement of behavioral performance. We have obtained novel results to support each of these outcomes and to illuminate their underlying molecular mechanisms.
In primary cortical neurons, we found that lithium and VPA selectively upregulated brain-derived neurotrophic factor (BDNF) promoter IV activity and exon IV-containing mRNA, and provided evidence that these effects are mediated by the inhibition of GSK-3 and HDACs, respectively. We demonstrated that VPA inhibition of class I HDACs induced functional heat shock protein 70 (HSP70) by enhancing its promoter activity via increased histone H3 acetylation and histone H3 lys4 methylation in primary neurons and astrocytes.
We have also advanced our understanding of the beneficial effects of mood stabilizers using experimental models of brain disorders. Using middle cerebral artery occlusion (MCAO) in rats as a model of focal cerebral ischemia, we found that post-insult treatment with VPA reduced infarct volume and improved behavioral outcomes. For the first time, we demonstrated that VPA robustly reduced blood-brain barrier (BBB) disruption induced by MCAO, and that this reduction was largely due to decreases in ischemia-induced matrix metalloproteinase 9 (MMP-9) overexpression and tight junction degradation. We also showed that long-term VPA treatment enhanced post-ischemic angiogenesis by increasing microvessel density, facilitating endothelial cell proliferation, and augmenting relative cerebral blood flow in the ipsilateral cortex by upregulating hypoxia inducible factor-1α (HIF-1α) and its downstream targets pro-angiogenic vascular endothelial growth factor (VEGF) and MMP-2/9. In addition, tail-vein injection of mesenchymal stem cells (MSCs) into MCAO rats was found to be highly beneficial when these MSCs were primed with both lithium and VPA to induce MMP-9 and CXC chemokine receptor 4 (CXCR4), respectively, thereby promoting MSC migration to the infarct region. Finally, we reported that HDAC inhibition by a VPA analog enhanced post-MCAO-induced neurogenesis in multiple ischemic brain regions, and that this effect required the activation of BDNF-TrkB signaling.
Huntington’s disease (HD) is an inherited, fatal neurodegenerative/neuropsychiatric disorder with no available treatment to halt symptom progression. We assessed the therapeutic potential of dietary treatment with lithium and/or VPA in two transgenic mouse models of HD, N171-82Q and YAC128, which both express mutant huntingtin protein (mHtt), but differ in symptom progression and lifespan. We detected hyperactivity of GSK-3 and HDACs in the brains of untreated HD mice, which correlated with the onset of behavioral symptoms. We then found that co-treatment with lithium and VPA more effectively alleviated impaired locomotion and depressive-like behaviors than mono-treatment in both models of HD mice, and more consistently elevated levels of BDNF and HSP70 in the brain. Additionally, this co-treatment improved motor skill learning and coordination in N171-82Q mice suppressed anxiety-like behaviors in YAC128 mice, and markedly prolonged the lifespan of N171-82Q mice.
We have also launched three projects into new research areas. (1) We are studying the regulation of miRNAs by mood stabilizers in order to identify novel miRNA-mediated signatures and mechanisms in three separate areas: in vitro neuroprotection, cerebral ischemia, and patient-derived lymphoblastoid cell lines from lithium responsive and non-responsive BD patients. Several prominent miRNAs have been identified in each of these projects, and their function and targets are currently being investigated. (2) Another new study evaluates the effects of lithium treatment in an experimental mouse model of traumatic brain injury (TBI). We recently reported that post-insult lithium treatment ameliorated TBI-induced lesion size, neurodegeneration, neuroinflammation, and functional impairments, in association with GSK-3 inhibition. Moreover, for the first time we showed that lithium blocked TBI-induced β-secretase overexpression, thereby decreasing β-amyloid burden and Tau protein hyperphosphorylation, as well as improving spatial memory performance. (3) We examined the neuroprotective properties of a third mood stabilizer, lamotrigine, which is also an anticonvulsant. Our results showed that lamotrigine robustly protected primary brain neurons from glutamate excitotoxicity, and that this protection required the induction of cytoprotective Bcl-2. We also showed for the first time that lamotrigine indirectly inhibited HDACs, thereby increasing Bcl-2 promoter activity by histone hyperacetylation. Interestingly, a sub-effective dose of lamotrigine showed synergistic neuroprotective effects when used in combination with lithium or VPA.
Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke. Wang Z, Tsai LK, Munasinghe J, Leng Y, Fessler EB, Chibane F, Leeds P, Chuang DM. Stroke. 2012 Sep;43(9):2430-6. doi: 10.1161/STROKEAHA.112.652545. Epub 2012 Jul 17. PMID: 22811460.
Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntingtons Disease. Chi-Tso Chiu, Guangping Liu, Peter Leeds, and De-Maw Chuang. Neuropsychopharmacology. 2011 November; 36(12): 2406–2421. PMID: 21796107.
Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model. Tsai LK, Wang Z, Munasinghe J, Leng Y, Leeds P, Chuang DM. Stroke. 2011 Oct;42(10):2932-9. doi: 10.1161/STROKEAHA.110.612788. Epub 2011 Aug 11. PMID: 21836090.
The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms. Tsai LK, Leng Y, Wang Z, Leeds P, Chuang DM. Neuropsychopharmacology. 2010 Oct;35(11):2225-37. doi: 10.1038/npp.2010.97. Epub 2010 Jul 7. PMID: 20613717.
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